Invasive fungal diseases (IFDs) cause millions of deaths each year and they are refractory to treatment. For instance, Candida albicans and Cryptococcus neoformans cause life-threatening invasive candidiasis and cryptococcosis, respectively. Patients at the greatest risk of developing these IFDs have weakened immune systems such as HIV positive individuals. The vulnerable population is increasing due to increasing numbers of immunosuppressed individuals receiving stem cell or organ transplants. Patients with candidiasis or cryptococcosis are treated with various antifungal drugs, but all antifungals have serious limitations due to human cell and organ toxicity, the emergence of resistant fungi, and the lack of sufficient fungicidal effect at safe doses. Even with the current antifungal therapies, these two IFDs are associated with dramatically increased medical costs, increased length of hospital stay, and one-year survival is only 12 to 90%, depending upon the patient population. Our proposal meets the critical need for improved antifungal therapeutics. A thick outer cell wall and secreted extracellular matrix rich in mannans, galactomannans, and mannoproteins help some pathogenic fungi including C. albicans and C. neoformans evade host defense. The C-type lectin receptor Dectin-2 on the surface of mammalian lymphocytes bind strongly to mannans in the fungal cell wall, matrix, and solubilized into tissue to signal an innate immune response to infection. We have strong preliminary data showing that truncated Dectin-2 functions in a liposomal membrane. Dectin-2-coated antifungal drug-loaded liposomes bind mannans in the cell-associated exopolysaccharide matrix of C. albicans and C. neoformans two orders of magnitude more efficiently than uncoated liposomes and kills both species an order of magnitude more efficiently. The overarching goal of this exploratory proposal is to demonstrate Dectin- 2-targeted antifungal loaded liposomes increase antifungal drug efficacy as compared to current antifungal drugs. In particular, we will show that Dectin-2-coated drug-loaded liposomes have enhanced antifungal activity toward C. albicans and C. neoformans in vitro and efficiently treat disseminated candidiasis in an in vivo mouse model. We have an established team of scientists already combining their expertise in diverse areas of science necessary to carry out these experiments including fungal biology and pathology, immunology and liposome biochemistry, genetics, and protein chemistry. Successful completion of this study will establish the feasibility of antifungal drug delivery specifically to fungal mannans that will ultimately improve outcomes of patients with candidiasis, aspergillosis, and cryptococcosis. We will have developed an experimental platform to rapidly innovate and optimize fungal mannan and biofilm targeted therapies that may be used to treat diverse life- threatening fungal infections and milder fungal infections of eyes, skin, toenails, and biomedical devices.